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Antiepileptic Drugs
There are numerous drugs used in the management of epilepsy. Here, let's divide them into those that impact or are impacted by the cytochrome P450 system and those that are not.
Divide the P450-related drugs into those that are affected by P450 and those that induce or inhibit it.
Levetiracetam
P450-related
Affected by P450 Metabolism
Benzodiazepines
- As mentioned, benzodiazepines are the first-line treatment for status epilepticus.
- A key side effect is respiratory suppression, so status epilepticus patients often have to be intubated.
- The different benzodiazepines undergo a variety of different phase 1 and phase 2 types of drug metabolism.
- Ethosuximide is first-line in absence seizures but it is limited to this seizure type.
- Indicate the oft-used mnemonic "SUX" because of its numerous side effects.
- We can remember these side effects with the acronym: EFGHIJ, which stands Ethosuximide can cause Fatigue, Gastrointestinal distress, Headaches, Itching (as well as urticaria), and the J stands for Stevens Johnson syndrome – a rare but potentially life-threatening rash.
- Note that we most commonly associate Stevens Johnson syndrome with lamotrigine.
- Like the benzodiazepines, its level is affected when there are changes to major drug metabolism mechanisms, especially cytochrome P450 changes.
- Lamotrigine is a broad-spectrum AED.
- Its primary side effect is drug-rash (most worrisome being Stevens Johnson syndrome (SJS)), which is often dose-related.
- The risk of SJS increases substantially with rapid escalation in the drugs dosing, so it must be titrated slowly.
- Lamotrigine is highly affected by medications that act on drug metabolism, especially UGT-mediated glucuronidation.
- Thus, the titration schedule is highly affected by concomitant antiepileptic drugs which affect UGT metabolism, such as valproic acid.
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Inducers of P-450 Metabolism
Carbamazepine
- Carbamazepine is indicated for focal seizures.
- One of its major side effects is blood dyscrasias (leukopenia and thrombocytopenia).
- It is an inducer of drug metabolism, including both P450 and UGT-mediated (Uridine diphosphate glucuronosyltransferase enzyme-mediated) degradation (glucuronidation).
- Phenobarbital is used for focal seizures.
- It is first-line therapy in neonates (although other medications are now also being used).
- It has numerous side effects, including sedation, but we indicate its withdrawal potential, most notably: there is significant psychological and physiological dependence from the down-regulation of GABA that occurs from chronic phenobarbital use. Thus, it requires an incredibly slow wean schedule to avoid substantial rebound anxiety when the medication is stopped.
- It can cause cardiorespiratory depression, like the benzodiazepines, so these systems must be closely monitored.
- It's a major drug metabolism inducer; it is known to act on a wide variety of cytochrome P450 isoforms (including CYP2C9 and 2C19) as well as other forms of drug biotransformation, including UGT-degradation.
- Phenytoin is indicated for focal seizures.
- As mentioned, it is one of the key second-line therapies for status epilepticus.
- It has numerous side effects, including nystagmus and ataxia; gingival hyperplasia and hirsutism; megaloblastic anemia; and the potential for teratogenicity, which is referred to as fetal hydantoin syndrome.
- It's a major drug metabolism inducer, as well, and also acts on numerous cytochrome P450 isoforms.
- Topiramate is a broad-spectrum AED that is more commonly used in migraine prophylaxis than seizures.
- One key side effect is kidney stones.
- Many other potential side effects exist including, rarely, secondary angle-closure glaucoma; weight loss in part due to making carbonated beverages taste lousy; numbness and tingling of the hands and feet (it's a carbonic anhydrase inhibitor); and teratogenicity – an increase in oral cleft defects.
- Although it is partially renally-excreted, it is also a cytochrome P450 inducer and undergoes significant P450 degradation.
- It's important to note that because topiramate is a P450 inducer, it can reduce the efficacy of oral contraceptives (as can the other P450 inducers). We mention this, here, because, as discussed, topiramate is widely prescribed to women of childbearing age for migraine prophylaxis.
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Inhibitor of P450 Metabolism
Valproic acid (VPA)
- Valproic acid is a broad-spectrum AED.
- One of its key side effects is hepatotoxicity.
- Very importantly, it is highly teratogenic in the first trimester, as it is a key cause of AED-associated neural tube defects.
- It is a major drug metabolism inhibitor (it inhibits a wide variety of biotransformation systems, including various cytochrome P450 isoforms and also UGT-mediated degradation (which is an especially important interaction with lamotrigine).
- Note that it's the only inhibitor in our AED list. Other less commonly used AEDs that are inhibitors of drug metabolism are: felbamate, rufinamide, and stiripentol.
Non-P450 Related (Modern)
- Levetiracetam is a broad-spectrum AED.
- Its major side effect is psychiatric issues: emotional irritability and suicidality.
- Note that all seizure medications are considered to have the potential for suicidality and thus all patients must be counseled about this possibility no matter which AED they are prescribed.
- Indicate that, similar to gabapentin, it is primarily eliminated via renal excretion, so it's unaffected by changes in drug metabolism systems.
- Brivaracetam shares the same mechanism as levetiracetam but is far more selective for synaptic vesicle protein 2A (SV2A).
- Lacosamide is used to treat focal seizures.
- Indicate that, rarely, can cause arrhythmia, so should be used with caution in patients with an underlying proarrhythmic condition or in those taking medications that affect cardiac conduction or cause PR prolongation.
- It can easily cause dizziness, especially within the first half-hour after taking it and especially when taken with other sodium channel blockers.
- It is eliminated by demethylation and it's unaffected by P450 or UGT-mediated degradation.
- It is renally excreted so one might expect to have to make adjustments to the dose in renal failure; however it seems to have many elimination pathways, so moderate changes in renal function do not appear to significantly affect the blood level of the drug. Only in severe renal failure, does the dose need to be reduced.
- Gabapentin is used to treat focal seizures.
- Its major limitation in seizure management is its inferior efficacy and its tendency to cause sedation.
- It is an important treatment in neuropathic pain (note that many pain and headache medications were originally used as seizure drugs).
- And it is unaffected by changes to drug metabolism systems because it is renally-excreted: it does not undergo major drug biotransformation – but is renally-excreted unchanged.
- Thus, changes in the P450 system does not affect its metabolism but renal failure does alter its excretion (and thus will increase effective blood levels).
- Vigabatrin is used in refractory focal seizures.
- A major side effect of vigabatrin is the potential for blindness.
- It is renally-excreted so it is unaffected by changes in drug metabolism mechanisms.